PROJECT SUMMARY/ABSTRACT This proposal details a comprehensive five-year training program for mentored career development in functional genomics applied to preventive cardiovascular medicine. The applicant seeks to use DNA-aptamer based proteomics profiling data from human plasma and genomics data to identify novel pathways in atherosclerotic pathogenesis that can then be studied using animal, cell and molecular biology techniques. The candidate is completing his clinical fellowship in cardiovascular medicine and will join the faculty at Beth Israel Deaconess Medical Center upon graduation. The outlined proposal builds on the candidate?s clinical training and strong background in molecular and cellular research following his Ph.D. in pharmacology to provide two new domains of expertise through a blend of laboratory work, didactic courses, workshops, and scientific conferences: bioinformatics in functional genomics and the use of murine models of cardiovascular disease. The candidate?s mentor is a recognized leader in multi-omics molecular profiling in population-based studies and translating these findings back to cell- and animal-based model systems. The scientific advisory committee has a distinguished mentoring record and vast expertise in human genomics, murine models of atherosclerosis and metabolism, and gene editing. The proposed research extends preliminary studies that integrated proteomics and genomics data in two large population-based studies to identify a novel association between the phosphatase PPM1G and plasma levels of apolipoprotein E (ApoE). This association was experimentally validated in vitro by knocking down PPM1G in a human hepatocyte model, which led to the significant and specific down-regulation of ApoE transcription and ApoE protein levels. The applicant now proposes to test the hypothesis that PPM1G is a novel regulator of ApoE biology and contributes to early atherosclerotic pathogenesis in vivo using mouse models. In Aim 1, the applicant will test whether knockdown of PPM1G modulates ApoE expression in mice. In Aim 2, the applicant will examine whether knockdown of PPM1G modulates atherosclerotic lesion formation in murine models. In Aim 3, the applicant will expand his functional genomics studies to identify additional novel pathways in atherosclerotic pathogenesis and test their functional effects in model systems. Despite tremendous progress in preventive cardiology, atherosclerotic cardiovascular disease remains the leading cause of mortality worldwide. This residual disease burden likely reflects important, undiscovered biological pathways that underlie atherogenesis and that are not yet effectively targeted by available therapies. This proposal aims to use emerging functional genomics approaches to identify novel pathways in early atherosclerotic disease. By highlighting novel pathways, this research may ultimately lead to new targets for preventive atherosclerotic therapy.